INTRODUCTION
Tramadol is an opioid agonist that may be used to treat moderate to moderately severe chronic pain in adults. It binds to opiate receptors in the central nervous system in a selective manner. Tramadol is changed into the active metabolite M1, which has a higher affinity for the mu receptor than the inactive form, by the liver enzyme CYP2D6. With an analgesic effectiveness up to six times that of tramadol, the M1 metabolite is demonstrated [1]. Tramadol has also non-opioid effects because it prevents monoamines like serotonin and norepinephrine from being reabsorbed. These monoamine neurotransmitters contribute to the central nervous system’s descending inhibitory pathways’ antinociceptive effects [2]. Tramadol relieves postoperative pain in a manner comparable to that of pethidine, and when combined with a non-opioid analgesic, its analgesic effectiveness can be further enhanced. Pain from trauma, renal or biliary colic, labor, and chronic pain of malignant or nonmalignant origin, especially neuropathic pain, can all be effectively managed and well alleviated [2].
It is known for its safety and good tolerance. Compared to other morphine-like substances, it has fewer side effects and lower potential for abuse or dependency. The most common side effects affecting 10% include nausea, dizziness, vomiting, drowsiness, tiredness, sweating and dry mouth, psychomotor agitation and heart arrhythmia. These side effects are typically acknowledged as being characteristic of opioids and are detailed in the product information. Anaphylactic and allergic reactions have been reported in a few cases, although the incidence was less than 0.1%, which is consistent with the widely held belief that opioids have a low incidence of these events [2].
Various opioids are strong histamine releasers, which can cause a range of hemodynamic abnormalities and possible allergic reactions. However, there is no clear and consistent correlation between the concentration of histamine in the blood and the occurrence of these effects [3].
Limited but conclusive research has been done on tramadol’s potential to release histamine.
Barth et al. examined 13 volunteers for possible side effects after giving them tramadol intravenously. Only skin reactions were found, however they were not classified as anaphylactoid because erythema and itching were only seen in 1 case after tramadol and 2 cases after saline. Furthermore, no changes in plasma histamine concentration were detected, and no systemic anaphylactoid reactions occurred. Blood pressure and heart rate were only slightly and temporarily elevated and there were no abnormalities in ECG readings. The only noted side effects were typical of opioid therapy [4].
CASE REPORT
We report the case of a 51-year-old woman with hypothyroidism, scoliosis, degenerative spine disease and multilevel discopathy who developed two episodes of anaphylactic shock. In 1990 after scoliosis surgery, the patient developed anaphylactic shock manifesting as dyspnea, blood pressure drop and fainting after being given an unknown painkiller (no medical documentation, data obtained from the patient’s report). The second episode of anaphylaxis with dyspnea and loss of consciousness developed after taking tramadol drops in 2003. She did not take angiotensin-converting enzyme inhibitors (ACEI) drug during both episodes. Since then the patient has been taking several painkillers due to severe spine pain, all of them belonging to nonsteroidal anti-inflammatory drugs (NSAIDs): diclofenac, ibuprofen, ketoprofen, paracetamol, acetylsalicylic acid, aceclofenac and piroxicam. However, these drugs used to have too little effect on the current intensity of pain. She was therefore admitted in June 2024 to our Allergology Unit with a suspected diagnosis of drug hypersensitivity to analgesics. The patient had also a history of idiopathic urticaria and lip angioedema that resolved with antihistamines and steroids and low-histamine diet. As probability of anaphylaxis to tramadol is extremely low, we decided to perform an allergy work-up covering tramadol and synthetic opioids, such as fentanyl, as well.
Informed consent was obtained from the patient for skin tests and drug challenges. During the allergy work-up a skin prick test (1 : 1 dilution) and an intradermal test (1 : 10 dilution) with fentanyl and a skin prick test (50 mg/ml) and an intradermal test (1 : 1000 and 1 : 100 dilutions, i.e. 50 µg/ml and 500 µg/ml) with tramadol were performed according to Australian and New Zealand Anesthetic Allergy Group Perioperative Anaphylaxis Investigation Guidelines [5]. The skin prick and intradermal tests with the parenteral preparation of fentanyl were negative. The skin prick test and intradermal test with tramadol with 1 : 1000 dilution were negative. The intradermal test with tramadol with 1 : 100 dilution proved to be positive, with wheal of 12 mm and flare of 40 mm. Thus the clinical signs and symptoms reported previously by the patient and the skin test results are consistent with an immediate hypersensitivity reaction.
There is therefore a high probability that the first reaction in the past was caused by tramadol.
The patient was discharged home with a recommendation not to use any form of tramadol in the future. Fentanyl was selected as a safe, strong painkiller.
DISCUSSION
Allergy to tramadol is perceived as extremely rare. Analysis of a cohort of subjects who experienced drug-related hypersensitivity leading to an emergency department visit revealed that frequency of anaphylaxis due to tramadol was 0.32%, that was 2/608 cases [6]. The current literature contains only a few publications about documented hypersensitivity reactions after the use of tramadol.
For the first time, in 2003, 1 case of life-threatening laryngeal edema and 5 cases of urticaria caused by tramadol were described by Asero in the report questioning the safety of tramadol, as an alternative to NSAID following NSAID-induced urticaria [7].
Then, in 2005 Hallberg and Brenning from a Pharmacovigilance Unit in Medical Products Agency in Sweden described 6 cases of tramadol-induced angioedema [8]. They additionally observed that ACEI might be related to a potential cause for tramadol-induced angioedema:
Case 1: A 52-year-old woman received tramadol as an add-on therapy due to headache following a fall trauma, after 2 days of the therapy, a swelling of the tongue and below her both eyes appeared. When tramadol was stopped, the symptoms vanished.
Case 2: A 36-year-old woman after the first dose of tramadol because of a pain of an unknown etiology revealed a swelling of the tongue, a difficulty in swallowing and pruritus with no rashes, thus tramadol was removed from her treatment.
Case 3: An 83-year-old woman with a suspicion of deep vein thrombosis in her left leg and concomitant erysipelas was treated with enoxaparin, cefuroxime, paracetamol, picosulfate, zopiclone and tramadol. After 5 days of treatment with tramadol she experienced a swelling of her throat. Only tramadol from the previous treatment was withdrawn, after the therapy with cortisone, antihistamines and adrenalin inhalation she improved and symptoms disappeared.
Case 4: A 79-year-old man took tramadol because of a back pain. After 17 days of the therapy he developed respiratory distress and a swelling of the tongue. After administration of cortisone, adrenalin and withdrawal of tramadol and ramipril, he recovered.
Case 5: A 61-year-old woman started tramadol due to a sciatic pain. Only after administration of the first dose she experienced a swelling of the tongue, respiratory distress and she had difficulty in opening a mouth. She was admitted to ICU where anti-allergy therapy was given with full recovery.
Case 6: A 55-year-old man received tramadol because of a pain in his right calf. After 5 days of treatment he developed a swelling of the tongue and edema of the oral cavity. The therapy with betamethasone and adrenaline was administered with fast improvement. Enalapril and tramadol were withdrawn [8].
Subsequently Grassman described the case of an elderly patient admitted for investigation of atypical chest pain. The only new agent started in the last 48 h was tramadol. The patient awoke in the morning with a tongue that was extremely swollen. However, it did not cause breathing difficulties. Similar episodes occurred in the past while taking ACEI. After therapy with nebulized adrenaline, hydrocortisone, chlorphenamine, ranitidine and oral doses of dexamethasone, edema subsided within 12 h [9].
The exact mechanism of tramadol-induced angioedema remains unknown. Its vasodilating effect is typically highlighted. By directly affecting the smooth muscle in the rabbit aorta and raising the endothelium’s production of nitric oxide (NO), tramadol causes vasodilation in vitro [10]. It is believed that ACEI also contribute to angioedema by enhancing vascular permeability and decreasing bradykinin inactivation, which results in vasodilatation [11].
In all cases described above, urticaria or angioedema occurred, but no generalized anaphylactic reaction was observed. However, in 2015 Mori et al. reported the first case of anaphylaxis to intravenous tramadol in a child. During the operation of varicocele in a 15-year-old boy the following general anesthetic drugs were administered: atropine, propofol, remifentanil, rocuronium, tramadol, ketoprofen and ranitidine. Before waking up from anesthesia he developed a severe anaphylactic reaction with trunk rash, laryngospasm, glottis edema and severe respiratory distress. After treatment with corticoids and epinephrine, he recovered. During hospitalization in the Allergy Unit he underwent oral provocation tests with ketoprofen and ranitidine (both negative) and he was tested with skin prick and intradermal tests for all used drugs (except ketoprofen). All skin prick tests were negative. Only an intradermal test with tramadol was positive with a wheal diameter of 6 mm in 1 : 10 dilution. An increased tramadol-specific IgE concentration was found. The authors suspected IgE-mediated immediate hypersensitivity to tramadol [12].
The next reported case of hypersensitivity to tramadol was described by Arslan in 2022. A 75-year-old patient with hypertension treated with ACEI underwent knee arthroplasty. After administration of 100 mg intravenous tramadol for postoperative pain the patient developed anaphylactic shock symptoms in 2 min: redness, itching, dyspnea, respiratory arrest and cardiovascular collapse. Treatment with methylprednisolone, pheniramine and fluids administered intravenously resulted in the return of spontaneous circulation and breathing. There was no use of adrenaline [13].
The last known report was published in 2024 by Saini et al., who described the single case of a systemic lupus erythematosus (SLE) patient who developed lethal angioedema after taking tramadol. A 23-year-old woman with lupus erythematosus experienced severe shoulder pain without any injuries. After receiving two intravenous injections of 50 mg tramadol at a nearby hospital, she was discharged home. The patient was readmitted to the hospital after developing rashes, swelling throughout the face and oral cavity, and steadily worsening lip and tongue swelling. The patient had no history of medication allergies. The patient was treated immediately with an intravenous injection of 100 mg hydrocortisone, one ampoule of 22.75 mg pheniramine maleate, and adrenaline nebulization. Although an emergency tracheostomy was advised, the patient’s family chose to exclusively use medical management. She consequently got supportive medical care. Regretfully, the patient died even after obtaining all necessary life-saving treatments [14].
In our patient, anamnestic data could have been considered as suggestive for tramadol hypersensitivity, however the culprit drug of the first reaction was not known and long period passed since both episodes. That is why we decided to check if this patient is still or really sensitive to tramadol. Interestingly neither European [15] nor American guidelines [16] included recommendations on nonirritating concentrations of tramadol for skin tests. In this situation we used Australian and New Zealand Anesthetic Allergy Group Perioperative Anaphylaxis Investigation Guidelines [5]. The results of the intradermal skin test were undoubtedly positive and adequate to confirm diagnosis of tramadol immediate hypersensitivity. To the authors’ best knowledge, there are no commercially available methods of estimation of IgE agains tramadol, so we did not perform any laboratory test to confirm the diagnosis.
CONCLUSIONS
Immediate hypersensitivity to tramadol may happen more often than it has been believed. The most common symptoms are angioedema and/or urticaria, particularly if tramadol is used together with ACEI. However, a severe anaphylactic reaction with involvement of many organs may also be induced by tramadol.
General practitioners, specialists, and allergists should be aware of the risk of such reactions when prescribing tramadol or diagnosing drug allergies.
